Pancreatic cancer is the fourth leading cause of cancer death in the United States. The five- year survival rate is only 5% because no diagnostic markers are available for early detection. Inflammation has emerged as an important risk factor for the development of many types of cancers including pancreatic cancer. We hypothesize that suppressing inflammation with the anti-inflammatory omega-3 polyunsaturated fatty acids (PUFAs) found in fish oil will suppress inflammation and subsequent pancreatic adenocarcinoma development. To test this hypothesis, we will use the cyclooxygenase 2 (COX-2) transgenic mouse model fed diets enriched in either the omega-3 fatty acid eicosapentaenoic acid (EPA) or the omega-6 fatty acid linoleic acid prior to the onset of pancreatitis. The COX-2 Tg mouse overexpresses the COX-2 gene which causes spontaneous pancreatitis and subsequent development of pancreatic adenocarcinomas. This model is highly relevant because high COX-2 expression is found in human pancreatitis and pancreatic cancer. Histopathological examination of the pancreata will be performed to determine if dietary EPA suppresses immune cell recruitment and subsequent pancreatitis leading to adenocarcinoma development. Cytokine gene expression in the pancreata and T cell subset analysis in draining lymph nodes will also be performed to establish whether the beneficial effects of EPA are linked to modulation of innate or adaptive immunity or both. Lipodomic analysis will also be carried out for prostanoid production and fatty acid composition of the pancreata to evaluate how these lipid changes correlate with alterations in pancreatitis. Identifying novel immune targets of suppressing inflammation by omega-3 PUFAs will provide the necessary data to propose additional focused experiments aimed at elucidating the immune mechanism(s) by which omega-3 PUFAs and inflammation regulate pancreatic cancer development. This data may show an important role for the omega-3 PUFAs, especially EPA, in cancer prevention because they are well known anti-inflammatory agents and are widely consumed by people in the United States. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is the fourth leading cause of cancer death and has a 5% five-year survival rate due to lack of early detection techniques. Chronic inflammation is linked to the etiology of many different diseases, including pancreatic cancer. We propose that dietary omega-3 PUFAs may help delay the onset of pancreatitis and slow the early stages of pancreatic cancer development. This project is relevant to public health because it will provide evidence for a new dietary strategy to delay the development of pancreatic cancer.